Antibodies and antibody-fusion proteins as anti-angiogenic, anti-tumor agents

Research output: Contribution to journalReview article

6 Scopus citations

Abstract

It is well established that the "switch" from an avascular to the vasculogenic phenotype is required for growth as well as metastasis of the tumor. Multiple regulators of angiogenesis, positive and negative, have been described. Due to the tumor growth dependence on angiogenesis, anti-angiogenic therapy is rapidly evolving as anticancer strategy. Antibodies and inhibitors directed against pro-angiogenic signaling proteins and growth factors pathways have been shown to mediate anti-tumor activity in preclinical models as well as in clinical trials. The development of anti-angiogenic antibody therapy had great impact in the treatment of human cancers. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody has been approved for the treatment of metastatic colorectal cancer. Other antibodies and Fc fusion proteins targeting VEGFR, nerve and blood vessel guidance pathways (Robo4), plasma membrane adhesion receptors (known as integrins) or selectively neutralizing the interaction between the angiopoietins and their receptors are being tested in preclinical models and clinical trials. Direct angiogenesis inhibitors have also been tested in an attempt to suppress pathologic angiogenesis. The prototypic anti-angiogenic peptides endostatin and angiostatin had generated enormous enthusiasm initially, but so far they have not fulfilled their promise in the human setting in part due to the instability of these proteins and their short serum half-lives. We have proposed increasing the effect of the anti-angiogenic agents by targeting them to the tumor microenvironment through the creation and optimization of anti-tumor anti-angiogenic peptide fusion proteins. We have tested this hypothesis using an antibody-endostatin fusion protein with specificity for the HER2/neu target antigen in breast and other solid tumors. Linkage of the endostatin to anti-HER2 antibody could expand the spectrum of anti-tumor activities of Herceptin by focusing the anti-angiogenic properties of endostatin on HER2 expressing targets and creating a multifunctional angiogenic inhibitor with powerful anti-tumor activity. Our data indicate that Traztuzumab targeting sequences fused with endostatin may possess significantly enhanced anti-angiogenic and anti-tumor activity. We anticipate therefore that such fusion proteins, could be combined with conventional chemotherapy, radiation, and surgical procedures and will prove superior to antibody (e.g. Traztuzumab) or endostatin administered alone. The combination of fusion protein with other angiogenic strategies such as PDGF blockade, VEGF blockade, thrombospondin-1 as well as with chemotherapy remains to be tested. Targeting anti-angiogenics using this and/or similar targeting strategies may in theory enhance the efficacy of this versatile approach and improve patient outcomes.

Original languageEnglish (US)
Pages (from-to)159-173
Number of pages15
JournalUpdate on Cancer Therapeutics
Volume1
Issue number2
DOIs
StatePublished - Jun 1 2006

Keywords

  • Angiogenesis
  • Anti-angiogenesis
  • Anti-angiogenic Fc fusion protein
  • Anti-tumor antibody
  • Antibody-fusion protein
  • Endostatin-fusion protein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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